1,2,4-Benzothiadiazines

ABSTRACT

Disclosed are compounds of the formula 
     
         R.sub.1 --Ar--(CH.sub.2).sub.a --X--(CH.sub.2).sub.b --NH--Het 
    
     wherein R 1  is guanidino or substituted guanidino, Ar is furandiyl, thiophendiyl, phenylene, pyridinediyl, pyrimidinediyl, thiazolediyl, thiadiazolediyl or imidazolediyl; a is 0, 1 or 2; b is 2, 3, 4 or 5; and Het is a bicyclic heteroary group, and pharmaceutically acceptable salts, quaternized derivatives, N-oxides and solvates thereof. The compounds are useful for the treatment or prophylaxis of disorders relating to excess gastric acid secretion in mammals.

The present invention relates to novel compounds having pharmacological activity, to processes and intermediates for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of mammals.

U.S. Pat. No. 4,128,658 discloses a class of aminoalkylfuran derivatives that are histamine H₂ -receptor antagonists and that, therefore, are useful in the treatment of disorders relating to excess gastric acid secretion. One such derivative is the compound, N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, which is commonly known as ranitidine.

A structurally distinct class of compounds has now been discovered. In addition, such compounds have been found to be histamine H₂ -receptor antagonists. They are, therefore, useful in the treatment of disorders relating to excess gastric acid secretion, such as peptic ulcer and Zollinger-Ellison syndrome.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof:

    R.sub.1 --Ar--(CH.sub.2).sub.a --X--(CH.sub.2).sub.b --NH--Het (I)

wherein:

R₁ is hydrogen, halogen, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, or amino or guanidino, the or any amino moiety being optionally substituted by one or two C₁₋₄ alkyl optionally substituted by halogen, or an aminomethylene group of formula (a), ##STR1## in which R₂ and R₃ are the same or different and are hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl or phenyl C₁₋₄ alkyl, or R₂ and R₃ together with the nitrogen atom to which they are attached are morpholino, pyrrolidino or piperidino;

Ar is furandiyl, thiophendiyl, phenylene, pyridinediyl, pyrimidinediyl, thiazolediyl, thiadiazolediyl or imidazolediyl;

a is O or an integer 1 or 2;

X is --S--, --O--, --CH₂ --, ##STR2## or --NH--;

b is an integer from 2 to 5; and

Het is a bicyclic heteroaryl group of formula, ##STR3## in which R₄ and R₅ are the same or different and are hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, nitro, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, carboxy, amino, aminocarbonyl, aminocarbonylamino, amino-thiocarbonylamino, aminosulphonyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonylamino, C₁₋₆ alkylsulphinylamino, phenylsulphonyl, phenylsulphinyl or are a group of formula (d) or (e),

    R.sub.9 --CY-- (d)     R.sub.9 --CY--Z-- (e)

in which R₉ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, phenyl, phenoxy or phenylthio, Y is oxygen or sulphur and Z is oxygen, sulphur or N-R₁₀, R₁₀ being hydrogen or C₁₋₆ alkyl, the C₁₋₆ alkyl group or the C₁₋₆ alkyl moiety of any of the foregoing C₁₋₆ alkyl-containing groups for R₄ and R₅ being optionally substituted by phenyl, the amino group or the amino moiety of any of the foregoing amino-containing groups for R₄ and R₅ being optionally substituted by one or two C₁₋₆ alkyl, phenyl or phenyl-C₁₋₄ alkyl or optionally N-disubstituted by C₄₋₅ polymethylene, and the phenyl moiety of any of the foregoing phenyl-containing groups for R₄ and R₅ being optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, nitro or trifluoromethyl, one of R₆ and R₈ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkanoyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkoxycarbonyl or phenoxycarbonyl, benzyloxycarbonyl, phenyl, phenylsulphonyl or phenyl C₁₋₄ alkyl, the phenyl moiety being optionally substituted by benzoyl, C₁₋₆ alkyl, C₁₋₄ alkoxy, halogen, nitro or trifluoromethyl, and the other of R₆ and R₈ together with R₇ is a bond, and n is O or an integer 1 or 2.

Examples of Ar include 2,5-furandiyl; 2,5-thiophendiyl; 1,3- and 1,4-phenylene; 2,3- and 2,4-pyridinediyl; 2,4-pyrimidinediyl; 2,4-thiazolediyl; 3,5-(1,2,4,)-thiadiazolediyl; and 2,4- and 4,5-imidazolediyl. Preferred examples of Ar include 2,5-furandiyl; 2,5-thiophendiyl; 1,3-phenylene; and 2,4-thiazolediyl. The most preferred example of Ar is 2,5-furandiyl.

When Ar is furandiyl, thiophendiyl or phenylene, R₁ is, preferably, an aminomethylene group of formula (a), as hereinbefore defined. In particular, R₁ is an aminomethylene group of formula (a), in which R₂ and R₃ are the same or different and are hydrogen, methyl, ethyl, cyclopropyl or cyclohexyl, or R₂ and R₃ together with the nitrogen atom to which they are attached are pyrrolidino or piperidino. Most preferably, R₁ is dimethylaminomethyl, pyrrolidinomethyl or piperidinomethyl.

When Ar is pyridinediyl, pyrimidinediyl, thiazolediyl, thiadiazolediyl or imidazolediyl, in particular thiazolediyl, R₁ is, preferably, hydrogen, halogen, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, or amino or guanidino, the or any amino moiety being optionally substituted by one or two C₁₋₄ alkyl optionally substituted by halogen, or an aminomethylene group of formula (a), as defined hereinbefore. In particular, R₁ is hydrogen, halogen, such as bromo, C₁₋₄ alkyl, such as methyl, or guanidino, any amino moiety being optionally substituted by one or two C₁₋₄ alkyl.

Preferred examples of a are O and the integer 1. In relation to the preferred examples of Ar, a is, preferably, the integer 1 when Ar is 2,5-furandiyl, 2,5-thiophendiyl or 2,4-thiazolediyl and is, preferably, O when Ar is 1,3-phenylene.

Preferred examples of X include --S--, --O-- and --CH₂ --, in particular --S-- and --O--.

Preferred examples of b are the integers 2, 3 and 4, especially the integers 2 and 3. In relation to the preferred examples of Ar, b is, preferably, the integer 2 when Ar is 2,5-furandiyl, 2,5-thiophendiyl or 2,4-thiazolediyl, and is, preferably, the integer 3 when Ar is 1,3-phenylene.

A sub-class of R₄ and R₅ is that wherein R₄ and R₅ are the same or different and are hydrogen, trifluoromethyl, nitro, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, or amino optionally substituted by one or two C₁₋₆ alkyl or phenyl C₁₋₄ alkyl or optionally N-disubstituted by C₄₋₅ polymethylene, or C₁₋₆ alkylsulphonyl or phenylsulphonyl, the phenyl moiety being optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, nitro or trifluoromethyl, or are a group of formula (d) in which Y is oxygen and R₉ is as defined hereinbefore, or are a group of formula (e) in which Y is oxygen, Z is N-R₁₀ and R₉ and R₁₀ are as defined hereinbefore.

A further sub-class of R₄ and R₅ is that wherein R₄ and R₅ are the same or different and are hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, nitro, cyano, C₁₋₆ alkoxy, or amino, aminocarbonylamino or aminosulphonyl, the amino moiety being optionally substituted by one or two C₁₋₆ alkyl, phenyl or phenyl-C₁₋₄ alkyl or optionally N-disubstituted by C₄₋₅ polymethylene, or C₁₋₆ alkylsulphonylamino or a group of formula (e) in which R₉ is hydrogen or C₁₋₆ alkyl, Y is oxygen and Z is NH.

Particular examples of R₄ and R₅, which may be the same or different, include hydrogen, chloro, bromo, iodo, methyl, trifluoromethyl, nitro, cyano, methoxy, amino, methylaminocarbonylamino, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, methylsulphonylamino, formamido, acetamido and propionamido.

Preferred examples of R₄ and R₅, which may be the same or different, include hydrogen, nitro, amino, methylaminosulphonyl, dimethylaminosulphonyl, acetamido and propionamido. In particular, one of R₄ and R₅ is hydrogen and the other is hydrogen, nitro, amino, methylaminosulphonyl, dimethylaminosulphonyl, acetamido and propionamido. The preferred position for substitution if a substituent is present for the other of R₄ and R₅ is the 7-position.

Preferably, one of R₆ and R₈ is hydrogen or C₁₋₆ alkyl, such as methyl, and the other of R₆ and R₈ together with R₇ is a bond. When one of R₆ and R₈ is C₁₋₆ alkyl, such as methyl, it is preferred that R₆ is so defined and R₈ together with R₇ is a bond.

Preferably, n is an integer 1 or 2, in particular 2.

The compounds of the present invention are capable of existing as tautomers. The present invention extends to all such tautomers individually and as mixtures.

A pharmaceutically acceptable salt of a compound of the present invention is, preferably, a pharmaceutically acceptable acid addition salt. Examples of such a salt include an inorganic acid addition salt, such as a sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide, and an organic acid addition salt, such as an acetate, fumarate, tartrate, citrate, succinate, benzoate, ascorbate, methylsulphonate, α-ketoglutarate, α-glycerophosphate and glucose-1-phosphate. The hydrochloride salt is the most preferred pharmaceutically acceptable salt.

A quaternised derivative of a compound of the present invention includes a compound of the present invention quaternised by an optionally substituted alkyl halide, for example, a C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₄ alkyl or phenyl C₁₋₄ alkyl halide, such as a chloride, bromide or iodide.

The compounds of the present invention and their pharmaceutically acceptable salts form solvates with pharmaceutically acceptable solvents, for example hydrates.

Of the compounds exemplified hereinafter those that are preferred include the compound of Example 5c.

The present invention also provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof, which comprises reacting a compound of formula (II), or an acid addition salt thereof:

    R.sub.1 --Ar--(CH.sub.2).sub.a --X--(CH.sub.2).sub.b --NH.sub.2 (II)

wherein R₁, Ar, a, X and b are as defined hereinbefore, with a compound of formula (III):

    Het--L.sub.1                                               (III)

wherein Het is as defined hereinbefore and L₁ is a leaving group; in the case where n in the resulting compound of formula (I) is O, optionally oxidising the compound to obtain another compound of formula (I) wherein n is an integer 1 or 2; optionally converting R₁, R₄, R₅, R₆ or R₈ in the resulting compound of formula (I) into another R₁, R₄, R₅, R₆ or R₈ ; and optionally forming a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof.

The leaving group (L₁) is such as to be displaceable by the compound of formula (II). Examples of the leaving group (L₁) include halogen, such as chloro and bromo, C₁₋₄ alkoxy, such as methoxy and ethoxy, C₁₋₄ alkylthio, such as methylthio and ethylthio, C₁₋₄ alkylsulphinyl, such as methylsulphinyl, and thiol. Preferred examples of the leaving group (L₁) include chloro, methoxy, ethoxy, methylthio and thiol. Particularly preferred examples are chloro and ethoxy.

The reaction may be carried out in a solvent, such as dichloromethane, toluene, 2-methoxy-ethanol, methanol, isopropanol, dimethylformamide or dimethoxyethane/methanol, at room temperature or above, for example, at reflux temperature, optionally in the presence of an acid acceptor, such as triethylamine.

In the case where an acid addition salt of a compound of formula (II) is used in the reaction, it is preferred that the leaving group (L₁) is halogen and that an acid acceptor is present during the course of the reaction. It is even more preferred, however, that the compound of formula (II) is used not in the form of an acid addition salt but in the form of its free base.

In the case where n in the resulting compound of formula (I) is O, the optional oxidation of the compound to obtain another compound of formula (I), wherein n is an integer 1 or 2, may be carried out with a metal, such as sodium, periodate or with one equivalent of m-chloroperbenzoic acid, when n is 1, or with an excess of m-chloroperbenzoic acid, when n is 2. It is preferred, however, that such oxidation is not carried out on a compound of formula (I), wherein X is --S--. It is even more preferred that any oxidation of this kind is carried out at an earlier stage in the process of the invention rather than on a compound of formula (I).

Examples of an optional conversion of R₁ in the resulting compound of formula (I) into another R₁ include the optional conversion of an aminomethylene group of formula (a), wherein R₂ and R₃ are hydrogen, into another aminomethylene group of formula (a), wherein R₂ or R₃ are C₁₋₄ alkyl. Such a conversion may be carried out by direct alkylation or by reductive alkylation.

Examples of an optional conversion of R₄ and/or R₅ in the resulting compound of formula (I) into another R₄ and/or R₅ include the optional conversion of hydrogen into nitro by nitration, nitro into amino by reduction, halogen into amino by amination, and amino, aminocarbonyl, aminocarbonylamino, amino-thiocarbonylamino and aminosulphonyl into amino, aminocarbonyl, aminocarbonylamino, amino-thiocarbonylamino and aminosulphonyl, the amino group or the amino moiety of the amino-containing groups being substituted by one or two C₁₋₆ alkyl, by alkylation or by reductive alkylation.

Examples of an optional conversion of R₆ or R₈ in the resulting compound of formula (I) into another R₆ or R₈ include the optional conversion of hydrogen into C₁₋₆ alkyl by alkylation.

The optional formation of a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate may be carried out conventionally.

The compounds of formula (II) are known, or can be prepared analogously to the preparation of known compounds, for example, from U.S. Pat. Nos. 3,905,984, 4,022,797, 4,053,473, 4,128,658, 4,165,378 and 4,220,654.

The compounds of formula (III) may be prepared by reacting a compound of formula (IV): ##STR4## wherein one of R₆ ' and R₈ ' is hydrogen or C₁₋₆ alkyl and the other is hydrogen, and R₄, R₅ and n are as defined hereinbefore, with urea or thiourea, and, in the case of urea reacting the resulting compound of formula (V): ##STR5## wherein one of R₆ " and R₈ " is hydrogen or C₁₋₆ alkyl and the other together with R₇ is a bond, and R₄, R₅ and n are as defined hereinbefore, with a halogenating agent; optionally converting the halogen or thiol leaving group (L₁) in the resulting compound of formula (III) into another leaving group (L₁); and optionally converting one of R₆ and R₈, when hydrogen, in the resulting compound of formula (III) into one of the other substituents defined hereinbefore.

The reaction of a compound of formula (IV) with either urea or thiourea may be carried out following the procedure of Parke and Williams (J. Chem. Soc., 1950, 1760).

Examples of a halogenating agent include thionyl halide, phosphorous oxyhalide and phosphorus pentahalide. A preferred example is phosphorus pentahalide.

The reaction of a compound of formula (V) with a halogenating agent may be carried out either by heating the reactants in neat form in a high boiling inert solvent, such as decalin, or in an excess of the halogenating agent as solvent optionally in the presence of a tertiary base, such as 2,6-lutidine, to a temperature of 100°-180° C. as appropriate.

The optional conversion of the halogen leaving group (L₁) in the resulting compound of formula (III) into another leaving group (L₁) may be carried out in accordance with conventional methods. For example, the resulting compound of formula (III) may be reacted with an appropriate C₁₋₄ alcohol or C₁₋₄ thioalcohol optionally in the presence of an acid halide acceptor, such as pyridine, or in an inert solvent, such as dichloromethane.

The optional conversion of the thiol leaving group (L₁) in the resulting compound of formula (III) into another leaving group (L₁) may be carried out in accordance with conventional methods. For example, the resulting compound of formula (III) may be reacted with an alkylating agent so as to obtain the corresponding compound of formula (III), wherein L₁ is C₁₋₄ alkylthio.

Examples of an optional conversion of one of R₆ and R₈, when hydrogen, in the resulting compound of formula (III) into one of the other substituents defined hereinbefore include those examples described hereinbefore in relation to the optional conversion of R₆ and R₈ in a resulting compound of formula (I).

The compounds of formula (IV) are known or may be prepared in an analogous manner to the preparation of known compounds.

The present invention provides a second process for preparing a compound of formula (I), wherein X is --S--, --O--, ##STR6## or --NH, or a pharmaceutically acceptable salt, quaternised derivative, N-oxde or solvate thereof, which comprises reacting a compound of formula (VI):

    R.sub.1 --Ar--(CH.sub.2).sub.a --L.sub.2                   (VI)

wherein R₁, Ar and a are as defined hereinbefore and L₂ is a leaving group, with a compound of formula (VII):

    H--X'--(CH.sub.2).sub.b --NH--Het                          (VII)

wherein b and Het are as defined hereinbefore and X' is --S--, --O--, ##STR7## or --NH--; in the case where n in the resulting compound of formula (I) is O, optionally oxidising the compound to obtain another compound of formula (I) wherein n is an integer 1 or 2; optionally converting R₁, R₄, R₅, R₆ or R₈ in the resulting compound of formula (I) into another R₁, R₄, R₅, R₆ or R₈ ; and optionally forming a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof.

The leaving group (L₂) is such as to be displaceable by the compound of formula (VII). Examples of the leaving group (L₂) include halogen, such as chloro and bromo, hydroxy, and mesyloxy and tosyloxy.

The reaction between the compounds of formulae (VI) and (VII) may be carried out conventionally using either a polar protic or aprotic solvent, in the presence of an acid acceptor, such as triethylamine or a metal carbonate, or in the presence of a strong acid, such as hydrochloric acid.

The optional oxidation may be carried out as described hereinbefore.

Examples of an optional conversion of R₁, R₄, R₅, R₆ or R₈ include those described hereinbefore.

The optional formation of a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate may be carried out as described hereinbefore.

The compounds of formula (VI) are either known, for example, from U.K. Patent Application No. 81 14 575, Spanish Pat. No. 506 422 and J. Chem. Soc., 1958, 4728 to 4731, or may be prepared in an analogous manner to the preparation of known compounds.

The compounds of formula (VII) may be prepared by reacting a compound of formula (III), as defined hereinbefore, with a compound of formula (VII):

    H--X'--(CH.sub.2).sub.b --NH.sub.2                         (VIII)

wherein b and X' are as defined hereinbefore.

The reaction between the compounds of formulae (III) and (VIII) may be carried out under the conditions described hereinbefore in relation to the reaction between the compounds of formulae (II) and (III).

The compounds of formula (VIII) are known compounds.

The present invention provides a third process for preparing a compound of formula (I), wherein R₁ is an aminomethylene group of formula (a), as defined hereinbefore, or a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof, which comprises reacting a compound of formula (IX):

    L.sub.3 CH.sub.2 --Ar--(CH.sub.2).sub.a --X--(CH.sub.2).sub.b --NH--Het (IX)

wherein Ar, a, X, b and Het are as defined hereinbefore and L₃ is a leaving group, with an amine of formula (X): ##STR8## wherein R₂ and R₃ are as defined hereinbefore; in the case where n in the resulting compound of formula (I) is O, optionally oxidising the compound to obtain another compound of formula (I) wherein n is an integer 1 or 2; optionally converting R₁, R₄, R₅, R₆ or R₈ in the resulting compound of formula (I) into another R₁, R₄, R₅, R₆ or R₈ ; and optionally forming a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof.

The leaving group (L₃) is such as to be displaceable by the amine of formula (X). Examples of the leaving group (L₃) include hydroxy, chloro, bromo, mesyloxy and tosyloxy.

The reaction between the compound of formula (IX) and the amine of formula (X) may be carried out under the conditions described hereinbefore in relation to the reaction between the compounds of formulae (VI) and (VII).

The optional oxidation may be carried out as described hereinbefore.

Examples of an optional conversion of R₁, R₄, R₅, R₆ and R₈ include those described hereinbefore.

The optional formation of a pharmaceutically acceptable salt, quaternised derivative, N-oxide, or solvate may be carried out as described hereinbefore.

The compounds of formula (IX) may be prepared by reacting a compound of formula (III), as defined hereinbefore, with a compound of formula (XI):

    L.sub.3 CH.sub.2 --Ar--(CH.sub.2).sub.a --X--(CH.sub.2).sub.b --NH.sub.2 (XI)

wherein L₃, Ar, a, X and b are as defined hereinbefore.

The reaction between the compounds of formulae (III) and (XI) may be carried out under the conditions described hereinbefore in relation to the reaction between the compounds of formulae (II) and (III).

The compounds of formula (XI) may be prepared by reacting a compound of formula (XII):

    L.sub.3 'CH.sub.2 --Ar--(CH.sub.2).sub.a L.sub.4           (XII)

wherein Ar and a are as defined hereinbefore, L₃ ' is hydroxy or protected hydroxy and L₄ is a preferential leaving group, with a compound of formula (XIII):

    HX--(CH.sub.2).sub.b --NR.sub.11 R.sub.12                  (XIII)

wherein X and b are as defined hereinbefore and R₁₁ and R₁₂ are both hydrogen, or one of R₁₁ and R₁₂ is hydrogen and the other is a protecting group, or both of R₁₁ and R₁₂ together are a protecting group; in the case where in the resulting compound L₃ is protected hydroxy, removing the protecting group; optionally converting the hydroxy leaving group (L₃) in the resulting compound into another leaving group (L₃); and in the case where in the resulting compound one of R₁₁ and R₁₂ or both of R₁₁ and R₁₂ together are a protecting group, removing the protecting group.

Examples of the group (L₃ '), when protected hydroxy, include tetrahydropyranyl.

The preferential leaving group (L₄) is such as to be displaceable (in preference to the group (L₃ ')) by the compound of formula (XIII). Examples of the preferential leaving group (L₄) include chloro, bromo, hydroxy, mesyloxy and tosyloxy. When L₄ is hydroxy and a is other than 1, it is preferred that L₃ ' is protected hydroxy.

In the case where one of R₁₁ and R₁₂ is hydrogen and the other is a protecting group, examples of a protecting group include C₁₋₄ alkanoyl.

In the case where both of R₁₁ and R₁₂ together are a protecting group, examples of a protecting group include phthalimidyl.

The reaction between the compounds of formulae (XII) and (XIII) may be carried out under the conditions described hereinbefore in relation to the reaction between the compounds of formulae (VI) and (VII).

The removal of a protecting group from the resulting compound, wherein the group (L₃ ') is protected hydroxy, may be carried out conventionally.

The optional conversion of the hydroxy leaving group (L₃) into another leaving group (L₃) may be carried out as described hereinbefore in relation to the leaving group (L₁).

The removal of a protecting group from the resulting compound, wherein one of or both together of R₁₁ and R₁₂ are a protecting group, may be carried out conventionally.

The present invention provides a fourth process for preparing a compound of formula (I), wherein R₁ is an aminomethylene group of formula (a), as defined hereinbefore, or a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof, which comprises reacting a compound of formula (XIV):

    H--Ar--(CH.sub.2).sub.a --X--(CH.sub.2).sub.b --NH--Het    (XIV)

wherein Ar, a, X, b and Het are as defined hereinbefore, with formaldehyde and a compound of formula (X), as defined hereinbefore; in the case where n in the resulting compound of formula (I) is 0, optionally oxidising the compound to obtain another compound of formula (I) wherein n is an integer 1 or 2; optionally converting R₁, R₄, R₅, R₆ or R₈ in the resulting compound of formula (I) into another R₁, R₄, R₅, R₆ or R₈ ; and optionally forming a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof.

The reaction between the compounds of formulae (XIV) and (X) and formaldehyde is a Mannich reaction and may be carried out under conventional Mannich reaction conditions, for example, in aqueous media in the presence of a strong acid, such as hydrochloric acid.

The optional oxidation may be carried out as described hereinbefore.

Examples of an optional conversion of R₁, R₄, R₅, R₆ or R₈ include those described hereinbefore.

The optional formation of a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate may be carried out as described hereinbefore

The compound of formula (XIV) may be prepared by reacting a compound of formula (III), as defined hereinbefore, and a compound of formula (XV):

    H--Ar--(CH.sub.2).sub.a --X--(CH.sub.2).sub.b --NH.sub.2   (XV)

wherein Ar, a, X and b are as defined hereinbefore.

The reaction between the compounds of formulae (III) and (XV) may be carried out under conditions described hereinbefore in relation to the reaction between the compounds of formulae (II) and (III).

The compounds of formula (XV) may be prepared by reacting a compound of formula (XVI):

    H--Ar--(CH.sub.2).sub.a --L.sub.5                          (XVI)

wherein Ar and a are as defined hereinbefore and L₅ is a leaving group, with a compound of formula (XIII), as defined hereinbefore; in the case where in the resulting compound one of R₁₁ and R₁₂ or both of R₁₁ and R₁₂ together are a protecting group, removing the protecting group.

The leaving group (L₅) is such as to be displaceable by the compound of formula (XIII). Examples of the leaving group (L₅) include chloro, bromo, hydroxy, mesyloxy and tosyloxy.

The reaction between the compounds of formulae (XVI) and (XIII) may be carried out under the conditions as described hereinbefore in relation to the reaction between the compounds of formulae (VI) and (VII).

The compounds of formulae (III), (VII), (IX) and (XIV) are novel intermediates and represent part of the present invention.

As mentioned hereinbefore, the compounds of formula (I), and their pharmaceutically acceptable salts, quaternised derivatives, N-oxides and solvates thereof, are histamine H₂ -receptor antagonists and, therefore, are able to inhibit gastric acid secretion. In this way, the compounds may be used in the treatment or prophylaxis of any disorder caused or exacerbated by excess gastric acid secretion, such as peptic ulcers.

Accordingly, the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I), as defined hereinbefore, or a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof, and a pharmaceutically acceptable carrier.

The composition of the present invention may be formulated for administration by any route, although in general oral administration is preferred. The composition may be in the form of a tablet, capsule, powder, granule, lozenge, suppository, reconstitutable powder, or a liquid preparation, such as an oral or sterile parenteral solution or suspension.

In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may take the form of a tablet or a capsule and may contain conventional excipients such as a binding agent, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.

The solid oral compositions of the present invention may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.

Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice.

A particular composition of the invention is a tablet containing the required amount of a compound of the invention in the form of a powder or granulate compressed in intimate mixture with a lubricant, such as magnesium stearate, a filler, such as microcrystalline cellulose, and a disintegrant, such as sodium starch glycollate.

Oral liquid preparations may be in the form of, for example, an emulsion, syrup, or elixir, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as a suspending agent, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; an emulsifying agent, for example lecithin, sorbitol monooleate, or acacia; a non-aqueous vehicle (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and a buffering agent can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except of course that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. However, the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

When appropriate the composition of the invention may be presented as a suppository for rectal or vaginal administration. Suitable unit dose forms include tablets, capsules and powders in sachets or vials, and preferred forms include shaped oral unit doses, such as tablets and capsules.

The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.

It will be appreciated of course that the quantity of the compound administered to the sufferer each day will depend on the usual factors such as the severity of the disease, and the weight of the sufferer and on the dose-response characteristics of the particular active ingredient. Suitably however it is believed that between 0.1 to 25 mg/kg/day of the compound will be administered to achieve satisfactory therapy. Such administration is conveniently effected with repeated dosing throughout the day of the composition in unit dose form.

By way of example, unit dose compositions will suitably contain from 5 to 2000 mg, more preferably from 10 to 1000 mg of the active ingredient.

The invention also provides a method of treatment or prophylaxis of disorders, such as peptic ulcers, in mammals including humans, caused or exacerbated by excess gastric acid secretion, which method comprises the administration to the mammal of an effective amount of the compound of formula I, as hereinbefore defined, or a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof.

The following Examples illustrate the compounds of the present invention.

EXAMPLE 1 N-[2-(5-Dimethylaminomethylfuran-2-ylmethylthio)ethyl]-7-dimethylsulphamoyl-1,2,4-benzothiadiazine-3-amine-1,1,-dioxide ##STR9## A stirred solution of 2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethylamine (0.33 g), 3-chloro-7-dimethylsulphamoyl-1,2,4-benzothiadiazine-1,1-dioxide (0.5 g) and triethylamine (0.21 ml) in isopropanol (50 ml) was heated under reflux for 3 hrs. On evaporation to dryness, aqueous sodium bicarbonate solution was added and the product extracted with chloroform (2×100 ml). Purification by column chromatography (silica, 10% MeOH/CHCl₃) afforded the title compound as a foam (0.3 g).

¹ H-NMR (CDCl₃) δ=2.38 (s, 6H), 2.71 (br s, 8H), 3.3-3.8 (m, 6H), 6.28 (2d, 2H), 7.15 (d, 1H), 7.80 (dd, 1H), 8.23 (d, 1H)

EXAMPLE 2 N-[3-(3-Piperid-1-ylmethylphenoxy)propylamino]-7-dimethylsulphamoyl-1,2,4-benzothiadiazine-3-amine-1,1-dioxide ##STR10## Following the procedure outlined in Example 1, the title compound was obtained as a foam.

¹ H NMR CDCl₃ (270 MHz) δ=1.4-1.55 (m, 2H), 1.55-1.72 (m, 4H), 1.95-2.10 (m, 2H), 2.5-2.8 (m, 10H including 2.68, s, 6H), 3.56 (t, 2H), 3.63 (s, 2H), 4.02 (t, 2H), 6.75-6.9 (m, 2H), 7.0 (s, 1H), 7.14-7.3 (m, 2H), 7.73 (dd, 1H), 8.17 (d, 1H)

Mass spectrum C₂₄ H₃₃ N₅ O₅ S₂ : Required 535.1923; Observed 535.1919

EXAMPLE 3 N-[2-(2-Guanidinothiazole-4-ylmethylthio)ethyl]-7-dimethylsulphamoyl-1,2,4-benzothiadiazine-3-amine-1,1-dioxide ##STR11## Following the procedure outlined in Example 1, the title compound was obtained as a foam. EXAMPLE 4 N-[3-(3-Piperid-1-ylmethylphenoxy)propylamino]-7-bromo-1,2,4-benzothiadiazine-3-amine-1,1-dioxide monohydrate ##STR12## Following the procedure outlined in Example 1, the title compound was obtained as a foam.

¹ H NMR (CDCl₃ δ 1.25-1.8 (m, 6H), 1.8-2.2 (m, 2H), 2.3-2.7 (m, 4H), 3.3-3.7 (m, 4H), 4.0 (t, 2H), 6.1-7.3 (m, 9H including 4H exchangeable with D₂ O, 7.5 (dd, 1H), 7.88 (d, 1H)

Following the procedure outlined in Example 1, the following further compounds were prepared.

EXAMPLE 5 N-[2-({5-Dimethylaminomethylfuran-2-yl)methylthio)ethyl]-2-methyl-1,2,4-benzothiadiazine-3-amine-1,1-dioxide ##STR13##

NMR (δ, CDCl₃) 7.85-7.0 (m, 4H), 6.14 (s, 2H), 5.6-5.3 (m, 1H), 4.8-3.25 (m, 9H including 3.75 s, 2H; 3.40, s, 2H and 3.35, s, 3H), 2.81 (t, 2H), 2.25 (s, 6H)

EXAMPLE 5b N-[2-({5-Dimethylaminomethylfuran-2-yl}methylthio)ethylamino]-4-methyl-1,2,4-benzothiadiazine-3-amine-1,1-dioxide ##STR14##

¹ H NMR CDCl₃ : δ=2.30 (s, 6H), δ=2.75 (t, 2H), δ=3.25-3.70 (m, 9H including 3.51, s, 5H; and 3.69, s, 2H), δ=6.17 (brs, 2H), δ=6.45 (brt, 1H), δ=7.0-8.0 (m, 4H)

EXAMPLE 5c N-[3-(3-Piperid-1-ylmethylphenoxy)propylamino]-4-methyl-1,2,4-benzothiadiazine-3-amino-1,1-dioxide ##STR15##

¹ H NMR d⁶ DMSO: δ=1.2-1.75 (m, 6H), δ=1.8-2.2 (m, 2H), δ=2.5-2.8 (m, 4H), δ=3.2-4.3 (m, 9H including 3.80, s, 3H and 4.09, t, 2H), δ=6.80-7.80 (m, 8H), δ=10.5-11.5 (m, 1H)

Mass spectrum C₂₃ H₃₀ N₄ O₃ S: Required 442.2039; Observed 442.2045

EXAMPLE 5d N-[3-(3-Piperid-1-ylmethylphenoxy)propyl]-7-nitro-1,2,4-benzothiadiazine-3-amine-1,1-dioxide monohydrochloride ##STR16##

¹ H-NMR d⁶ DMSO: δ=1.25-2.3 (m, 8H including 2.05, t, 2H), δ=2.75-3.75 (m, 6H including 3.50, t, 2H), δ=4.14 (t, 2H), δ=4.29 (s, 2H), δ=6.90-7.60 (m, 5H), δ=7.75-8.0 (m, 1H), δ=8.30-8.55 (m, 2H), δ=10.0-12.5 (m, 2H)

EXAMPLE 5e N-[3-(3-Piperid-1-ylmethylphenoxy)propyl]-6-trifluoromethyl-1,2,4-benzothiadiazine-3-amine-1,1-dioxide monohydrochloride ##STR17##

¹ H NMR d⁶ DMSO: δ=1.0-2.25 (m, 8H including 2.02, t, 2H), δ=2.60-3.75 (m, 6H), δ=3.80-4.40 (m, 4H), δ=6.95-8.1 (m, 8H), δ=10-10.6 (m, 1H), δ=11.5-11.9 (m, 1H)

Mass spectrum C₂₃ H₂₇ N₄ O₃ F₃ S: Required 496.1756; Observed 496.1760

EXAMPLE 5f N-[3-(3-Piperid-1-ylmethylphenoxy)propyl]-3,7-diamino-1,2,4-benzothiadiazine-1,1-dioxide ##STR18##

A suspension of electrolytic iron (400 mgs) in a solution of N-[3-(3-piperid-1-ylmethylphenoxy)propyl]-7-nitro-1,2,4-benzothiadiazine-1,1-dioxide (0.4 g) in 5N hydrochloric acid (18 ml) and ethanol (15 ml) was stirred at room temperature for 4 hrs. On basification (K₂ CO₃), the product was extracted with ethylacetate (3×100 ml) and dried (Na₂ SO₄). Concentration and purification by column chromatography (silica, 10% MeOH/CHCl₃) afforded the title compound as a foam (200 mgs).

¹ H NMR d⁶ DMSO: δ=1.1-1.75 (m, 6H), δ=1.8-2.2 (m, 2H), δ=2.3-2.7 (m, 4H), δ=3.2-3.5 (brq, 2H), δ=3.67 (s, 2H), δ=4.05 (t, 2H), δ=4.75-5.5 (m, 2H), δ=6.60-7.50 (m, 8H), δ=10.50 (brs, 1H)

Mass spectrum C₂₂ H₂₇ N₅ O₃ S: Required 443.1991; Observed 443.1988

EXAMPLE 6 N-[2-({5-Dimethylaminomethylfuran-2-yl}methylthio)ethyl]-1,2,4-benzothiadiazine-3-amine-1,1-dioxide ##STR19##

A mixture of 3-methylthio-1,2,4-benzothiadiazole-1,1-dioxide (0.25 g) and 2-[(5-dimethylaminomethylfuran-2-yl)methylthio]-ethylamine (0.22 g) was heated to 160° for 1 hour. On cooling, the residue was dissolved in chloroform (3 ml) and purified by column chromatography (silica, chloroform/3% methanol) to give the N-[2-({5-dimethylaminoethylfuran-2-yl}methylthio)-ethyl]-1,2,4-benzothiadiazine-3-amine-1,1-dioxide (0.20 g, 55%) as a foam.

NMR (δ, CDCl₃) 7.95-7.75 (d,d, 1H, aromatic 8H), 7.6-6.5 (m, 5H, aromatic H+NH) 6.18 (s, 2H), 3.70 (s, 2H, N CH₂ -aryl), 3.65-3.3 (m, 4H, S-CH₂ -aryl+N--CH₂ --C ) 2.71 (br tr., 2H, S--CH₂ --C ) 2.35 (s, 6H, NCH₃)

m.s. Observed 394.1134, Theory 394.1134 for C₁₇ H₂₂ N₄ O₃ S₂

EXAMPLE 7 N-[3-(3-{1-piperidylmethyl}phenoxy)propyl]-1,2,4-benzothiadiazine-3-amine-1,1-dioxide ##STR20##

Following the procedure described in Example 6; N-[3-(3-{1-piperidylmethyl}phenoxy)propyl]-1,2,4-benzothiadiazine-3-amine-1,1-dioxide was obtained as a foam (0.2 g, 47%)

NMR (δ, CDCl₃) 7.9-6.4 (m, 10H, aromatic H and NH), 3.99 (br tr, 2H, OCH₂ --C ), 3.7-3.3 (m, 4H, aryl-CH₂ --N and NCH₂ --C ), 2.65-2.25 (m, 4H, piperidyl N-CH₂ --C ), 2.15-1.8 (m, 2H, aliphatic H), 1.75-1.25 (m, 6H, aliphatic H)

PHARMACOLOGICAL DATA SECTION

The ability of the compounds of the invention to modify the pH of gastric acid secretion was investigated as follows:

The perfused rat stomach preparation

The modified (1) perfused stomach preparation (2) of the urethane (25% solution) anaesthetised rat, maintained at 37° C., allows the continuous measurement of pH during basal and stimulated acid secretion.

The lumen of the stomach of male Wistar rats (approximately 200 g bodyweight) was perfused, via a cannula designed to reduce the dead space of the stomach, with 5% glucose solution (37° C.) at the rate of 3 ml/min. The perfusate was forced over the surface of the secretory mucosa only, the antrum being excluded. The effluent then passed over a microflow-type glass pH electrode via a collecting funnel situated in the non-glandular forestomach.

The secretagogue histamine was administered as a constant intravenous infusion to produce a steady rate of acid secretion. Test compounds were administered in solution as bolus intravenous injections and any effect on the pH of the perfusate noted. The perfusate pH was recorded on a potentiometric recorder and anti-secretory responses were measured in terms of the maximal reduction in hydrogen-ion concentration expressed as a percentage of the control concentration.

See Table I.

References:

(1) Ghosh, M. N. and Schild, H. O. (1958). Br. J. Pharmacol., 13, 54-61.

(2) Parsons, M. E. (1970). Ph.D. Thesis, University of London.

                  TABLE I                                                          ______________________________________                                         Compound of     Dose                                                           Example No.     (μmole/kg)                                                                            Inhibition                                           ______________________________________                                         6               0.5       78%                                                  7               0.5       94%                                                  ______________________________________                                    

Guinea-pig isolated atria

This test is designed to specifically detect histamine H₂ -receptor antagonists. Guinea-pigs of either sex, weighing between 250 and 500 g, were killed by cervical dislocation and exsanguination. The heart was removed and placed in cold McEwens solution. The atria were dissected free and mounted in a jacketed 5 ml capacity tissue bath containing McEwens solution maintained at 32° C. and gassed with a 95% oxygen, 5% carbon dioxide gas mixture. Atrial beating was detected by an auxotonic lever and from thence recorded on a Devices MX2 hot wire pen recorder. Atrial rate was derived from the amplified force signal using a Devices Instantaneous Ratemeter and recorded on the MX2 pen recorder. The addition of histamine to the tissue bath resulted in increases in both the rate and force of atrial beating. To avoid disruption of the tissue by repeated washing, responses to cumulative concentrations of histamine were obtained in the absence (control) and then presence of various concentrations of test compounds. The ability to antagonise histamine mediated positive chronotropic responses of this tissue is believed to be specific for H₂ -receptor antagonists. Such activity was assessed by examining the ability of test compounds to shift to the right the plotted concentration/response curves to histamine. A less than 5-fold decrease in histamine potency was taken as inactive, 5-10 fold as slightly active and 10 fold or greater as active.

See Table II.

                  TABLE II                                                         ______________________________________                                         Compound                                                                       of Example Concentration                                                                              Activity (Decrease in                                   No.        Molar       Histamine Potency)                                      ______________________________________                                         6          1 × 10.sup.-6                                                                        Active                                                  ______________________________________                                    

Toxicity

No drug-induced toxic effects were observed in these tests. 

I claim:
 1. A compound of formula (I), or a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof:

    R.sub.1 --Ar--(CH.sub.2).sub.a --X--(CH.sub.2).sub.b --NH--Het (I)

wherein: R₁ is guanidino, any amino moiety being optionally substituted by one or two C₁₋₄ alkyl optionally substituted by halogen, or an aminomethylene group of formula (a), ##STR21## in which R₂ and R₃ are the same or different and are hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl or phenyl C₁₋₄ alkyl, or R₂ and R₃ together with the nitrogen atom to which they are attached are morpholino, pyrrolidino or piperidino; Ar is furandiyl, thiophendiyl, phenylene, pyridinediyl, pyrimidinediyl, thiazolediyl, thiadiazolediyl or imidazolediyl; a is O or an integer 1 or 2; X is --S--, --O--, --CH₂ --, ##STR22## or --NH--; b is an integer from 2 to 5; and Het is a bicyclic heteroaryl group of formula, ##STR23## in which R₄ and R₅ are the same or different and are hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, nitro, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, carboxy, amino, aminocarbonyl, aminocarbonylamino, amino-thiocarbonylamino, aminosulphonyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonylamino, C₁₋₆ alkylsulphinylamino, phenylsulphonyl, phenylsulphinyl or are a group of formula (d) or (e),

    R.sub.9 --CY--  (d)     R.sub.9 --CY--Z--  (e)

in which R₉ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, phenyl, phenoxy or phenylthio, Y is oxygen or sulphur and Z is oxygen, sulphur or N--R₁₀, R₁₀ being hydrogen or C₁₋₆ alkyl, the C₁₋₆ alkyl group or the C₁₋₆ alkyl moiety of any of the foregoing C₁₋₆ alkyl-containing groups for R₄ and R₅ being optionally substituted by phenyl, the amino group or the amino moiety of any of the foregoing amino-containing groups for R₄ and R₅ being optionally substituted by one or two C₁₋₆ alkyl, phenyl or phenyl-C₁₋₄ alkyl or optionally N-disubstituted by C₄₋₅ polymethylene, and the phenyl moiety of any of the foregoing phenyl-containing groups for R₄ and R₅ being optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, nitro or trifluoromethyl, one of R₆ and R₈ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkanoyl, C₁₋₆ alkylsulphonyl, C₁₋₆ alkoxycarbonyl or phenoxycarbonyl, benzyloxycarbonyl, phenyl, phenylsulphonyl or phenyl C₁₋₄ alkyl, the phenyl moiety being optionally substituted by benzoyl, C₁₋₆ alkyl, C₁₋₄ alkoxy, halogen, nitro or trifluoromethyl, and the other of R₆ and R₈ together with R₇ is a bond, and n is O or an integer 1 or
 2. 2. A compound according to claim 1, wherein Ar is 2,5-furandiyl; 2,5-thiophendiyl; 1,3-phenylene; or 2,4-thiazolediyl.
 3. A compound according to claim 1, wherein Ar is furandiyl, thiophendiyl or phenylene and R₁ is an aminomethylene group of formula (a), as defined in claim
 1. 4. A compound according to claim 1, wherein Ar is thiazolediyl and R₁ is guanidino, any amino moiety being optionally substituted by one or two C₁₋₄ alkyl.
 5. A compound according to claim 1, wherein a is 0 and the integer
 1. 6. A compound according to claim 1, wherein X is --S--, --O-- or --CH₂ --.
 7. A compound according to claim 1, wherein b is an integer 2, 3 or
 4. 8. A compound according to claim 1, wherein R₄ and R₅ are the same or different and are hydrogen, trifluoromethyl, nitro, cyano, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkylthio, or amino optionally substituted by one or two C₁₋₆ alkyl or phenyl C₁₋₄ alkyl or optionally N-disubstituted by C₄₋₅ polymethylene, or C₁₋₆ alkylsulphonyl or phenylsulphonyl, the phenyl moiety being optionally substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, nitro or trifluoromethyl, or are a group of formula (d) in which Y is oxygen and R₉ is as defined in claim 1, or are a group of formula (e) in which Y is oxygen, Z is N-R₁₀ and R₉ and R₁₀ are as defined in claim
 1. 9. A compound according to claim 1, wherein R₄ and R₅ are the same or different and are hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, nitro, cyano, C₁₋₆ alkoxy, or amino, aminocarbonylamino or aminosulphonyl, the amino moiety being optionally substituted by one or two C₁₋₆ alkyl, phenyl or phenyl-C₁₋₄ alkyl or optionally N-disubstituted by C₄₋₅ polymethylene, or C₁₋₆ alkylsulphonylamino or a group of formula (e) in which R₉ is hydrogen or C₁₋₆ alkyl, Y is oxygen and Z is NH.
 10. A compound according to claim 9, wherein R₄ and R₅ are the same or different and are hydrogen, chloro, bromo, iodo, methyl, trifluoromethyl, nitro, cyano, methoxy, amino, methylaminocarbonylamino, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, methylsulphonylamino, formamido, acetamido and propionamido.
 11. A compound according to claim 10, wherein one of R₄ and R₅ is hydrogen and the other is hydrogen, bromo, trifluoromethyl, nitro, amino, dimethylaminosulphonyl.
 12. A compound according to claim 1 wherein n is 1 or
 2. 13. A compound according to claim 1 selected from the group consisting of:N-[2-((5-dimethylaminomethylfuran-2-yl)methylthio)ethyl]-2-methyl-1,2,4-benzothiadiazine-3-amine-1,1-dioxide; N-[2-((5-dimethylaminomethylfuran-2-yl)methylthio)ethylamino]-4-methyl-1,2,4-benzothiadiazine-3-amine-1,1-dioxide; N-[3-(3-piperid-1-ylmethylphenoxy)propylamino]-4-methyl-1,2,4-benzothiadiazine-3-amino-1,1-dioxide; andpharmaceutically acceptable salts, quaternised derivatives, N-oxides or solvates thereof.
 14. A pharmaceutical composition for the treatment or prophylaxis of disorders relating to excess gastric acid secretion in mammals, which comprises an effective amount of a compound of formula (I), as defined in any one of claims 1-12 or 13 or a pharmaceutically acceptable salt, quaternised derivative, N-oxide or solvate thereof, and a pharmaceutically acceptable carrier.
 15. A method for the treatment or prophylaxis of excess gastric acid secretion in mammals, which method comprises administering to the mammal an effective amount of a compound of formula (I), as defined in any one of claims 1-12 or 13, or a pharmaceutically acceptable salt, N-oxide or solvate thereof. 